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Anti-Saccharomyces cerevisiae autoantibodies (ASCAs) are considered specific for Crohn's disease. A growing number of studies have detected high levels of ASCAs in patients affected with autoimmune diseases. The autoantigen ''u2 snRNP B'' was found to conserve a superfamily protein domain that shares 83 % of the mannan sequence.
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Anti-Saccharomyces Cerevisiae Autoantibodies in Autoimmune Diseases From Bread Baking to Autoimmunity
Anti-Saccharomyces cerevisiae autoantibodies (ASCAs) are considered specific for Crohn's disease. A growing number of studies have detected high levels of ASCAs in patients affected with autoimmune diseases. The autoantigen ''u2 snRNP B'' was found to conserve a superfamily protein domain that shares 83 % of the mannan sequence.
Anti-Saccharomyces cerevisiae autoantibodies (ASCAs) are considered specific for Crohn's disease. A growing number of studies have detected high levels of ASCAs in patients affected with autoimmune diseases. The autoantigen ''u2 snRNP B'' was found to conserve a superfamily protein domain that shares 83 % of the mannan sequence.
Anti-Saccharomyces cerevisiae Autoantibodies in Autoimmune
Diseases: from Bread Baking to Autoimmunity
Maurizio Rinaldi & Roberto Perricone & Miri Blank & Carlo Perricone & Yehuda Shoenfeld #Springer Science+Business Media New York 2013 Abstract Saccharomyces cerevisiae is best known as the bakers and brewers yeast, but its residual traces are also frequent excipients in some vaccines. Although anti-S. cer- evisiae autoantibodies (ASCAs) are considered specific for Crohns disease, a growing number of studies have detected high levels of ASCAs in patients affected with autoimmune diseases as compared with healthy controls, including anti- phospholipid syndrome, systemic lupus erythematosus, type 1 diabetes mellitus, and rheumatoid arthritis. Commensal microorganisms such as Saccharomyces are required for nutrition, proper development of Peyers aggregated lym- phoid tissue, and tissue healing. However, even the com- mensal nonclassically pathogenic microbiota can trigger autoimmunity when fine regulation of immune tolerance does not work properly. For our purposes, the protein data- base of the National Center for Biotechnology Information (NCBI) was consulted, comparing Saccharomyces mannan to several molecules with a pathogenetic role in autoimmune diseases. Thanks to the NCBI bioinformation technology tool, several overlaps in molecular structures (50100 %) were identified when yeast mannan, and the most common autoantigens were compared. The autoantigen U2 snRNP B was found to conserve a superfamily protein domain that shares 83 % of the S. cerevisiae mannan sequence. Furthermore, ASCAs may be present years before the diag- nosis of some associated autoimmune diseases as they were retrospectively found in the preserved blood samples of soldiers who became affected by Crohns disease years later. Our results strongly suggest that ASCAs role in clinical practice should be better addressed in order to evaluate their predictive or prognostic relevance. Keywords Anti-Saccharomyces cerevisiae autoantibodies . Autoimmune diseases . Molecular mimicry . Autoantigenicity . Vaccines Introduction Saccharomyces cerevisiae, also known as the bakers or brewers yeast, has long been utilized to ferment the sugars of rice, wheat, barley, and corn to produce alcoholic bev- erages, and in the baking industry to raise dough. Thousands of years ago, yeasts accidentally contaminated flour or drinks, and the results were pleasant for the people who tasted them. As a consequence, we are now commonly exposed to yeast [1]. Nonetheless, anti-S. cerevisiae anti- bodies (ASCAs), directed against the phosphopeptido- mannan part of the cell wall of the yeast, have been identified as an important and specific serological marker for Crohns disease (CD) [2]. Furthermore, ASCAs were detected retrospectively as being present years before CD clinical onset in 31.3 % of preserved blood samples of Israeli Defence Force soldiers compared to none of the controls [3]. The pathogenic significance of ASCAs is not yet fully understood, but molecular mimicry of self-antigens remains a possibility. Although ASCAs are considered specific for CD, a growing number of studies have individually identi- fied high levels of ASCAs in other autoimmune diseases such as antiphospholipid syndrome (APS) [2], systemic M. Rinaldi : R. Perricone Rheumatology, Allergology and Clinical Immunology, Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy M. Blank : Y. Shoenfeld (*) Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Ramat Gan, Tel Aviv, Israel e-mail: shoenfel@post.tau.ac.il C. Perricone Reumatologia, Dipartimento di Medicina Interna e Specialit Mediche, Sapienza Universit di Roma, Rome, Italy Clinic Rev Allerg Immunol DOI 10.1007/s12016-012-8344-9 lupus erythematosus (SLE) [4], diabetes mellitus type 1 [5], and rheumatoid arthritis (RA) [6]. In recent decades, the pathogenesis of autoimmune diseases has increasingly come to be understood as a multifactorial process which develops through the interaction of the pebbles of genetic, immunological, environmental, and hormonal fac- tors which combine to compose the complex mosaic of auto- immunity [710]. Evidence of the association between ASCAs and autoimmune disorders has increased over the past two decades, and to the best of our knowledge, this is the first review aimed at discussing these findings and providing the molecular background for further studies. Environment/Infections and Autoimmunity The immune system is exposed to different antigens from the very first stages of its development and maturation. Positive selection allows weakly self-binding lymphocytes to survive, while negative selection leads to the accomplish- ment of the death program for cells interacting too tightly with immunogenic molecules, with the aim of maintaining self-tolerance. Only a very small minority of lymphocytes will survive and interact with several microbial antigens that could potentially cause pathology. The burden of infections dealt with from childhood makes every individuals micro- bial pattern unique [11]. Microbial agents can induce auto- immunity through four main mechanisms [12]: (1) molecular mimicry is perhaps the most likely mechanism and occurs when shared epitopes (carbohydrate, protein/ peptides, or DNA) in the pathogen and hosts molecular structures cross-react in the presence of an active immune response. Cross-reactivity is confirmed by the association between the pathogen and the autoimmune disease, the elicitation of the specific immune response, active immuni- zation or autoantigen-induced disease in animal models, and passive immunization if the disease occurs either after autor- eactive T cell or autoantibody administration in animal models. (2) Epitope spreading is the distinction from the original shared sequence after an antigen is processed and presented on the cell surface by antigen-presenting cells (APCs) which results in a new autoreactive response direct- ed against the neo-epitope, as occurs for rheumatoid factor (RF) mimicking collagen or laminin in chronic rheumatic heart disease [13]. (3) Bystander activation is based on the release of sequestered antigens as a consequence of tissue damage, usually due to viral infections, and involves autor- eactive lymphocytes previously not committed. Further- more, a pro-inflammatory microenvironment can switch on an autoimmune response in a bystander manner, killing adjacent healthy cells too [14]. (4) Persistent activation of the immune response, particularly during recurrent viral load increases, can lead to autoimmunity. Indeed, in mixed cryoglobulinemia, chronic HCV infection causes prolonged stimulation of the immune system which can drive the activation of the humoral immune response to produce monoclonal and polyclonal autoantibodies [15]. Toll-like receptors (TLRs), as an important part of the innate immu- nity and as effector molecules leading to the adaptive im- mune response, can detect fungal, viral, and bacterial pathogens that expose their conserved pathogen-associated molecular patterns [18]. The lack of TLR3 in mice has been associated with an ineffective immune response to CMV, while rare human mutations in TLR3 or UNC93B and in interleukin-1 receptor-associated kinase 4 or MyD88 result in recessive susceptibility to HSV-1 encephalitis and recur- rent bacterial infections, respectively [16]. The role of TLRs has only very recently been considered important in dealing with fungal infections, particularly by yeasts such as Can- dida spp.; TLR1, TLR3, TLR4, and TLR6 are all involved in the MyD88 molecular downstream pathway, transducing fungal danger signals [17]. Notably, TLR3 stimulation was linked with the improvement of T1D in models and experimental autoimmune encephalomyelitis before the L412F variant of TLR3 had been found in patients with chronic mucocutaneous candidiasis (in the absence of po- tentially related AIRE, LYP, dectin 1, or CARD9 mutations) [16]. The mucosal surface is the main localization site of the recently defined CD4 + Th17 lymphocytes which release IL- 17, involved in the response to extracellular bacterial and fungal infections. Saprophytic microbial flora is likely to maintain the delicate Th17-T regulatory (Treg) balance in gut-associated lymphoid tissue, one of the most important human barriers to external environmental factors. Nonethe- less, dysregulated IL-17 secretion drives immune-mediated pathology in the gut, notably inflammatory bowel disease (IBD) [19]. Thus, even the commensal nonclassically path- ogenic microbiota can trigger autoimmunity when fine reg- ulation of immune tolerance does not work properly [20]. Dietary components can also impact on Th17 activity since gliadin-specific Th17 cells have been characterized from biopsies of celiac patients [21], and vitamin D receptor- deficient experimental models were found to develop more severe IBD with IL-17 overexpression [22]. There is a lack of data concerning the effect that dietary intake of the brewer and bakers yeast S. cerevisiae may induce on Th17 cells. Currently, Th17 cells are deemed to play a role in the devel- opment and relapse of many autoimmune diseases, especially multiple sclerosis, RA, CD, and psoriasis [18]. Inflammation and cell stress amplify posttranscriptional regulation mecha- nisms increasing expression of microRNAs (miRNAs). MicroRNAs are emerging as posttranscriptional regulators of many biological processes including cellular proliferation, differentiation, and apoptosis with clinical implications for cancer and autoimmune diseases [23]. TNF-, IFN-, and several TLRs can induce miR155 in macrophages [24], and its Clinic Rev Allerg Immunol overexpression has also been described in response to the eukaryotic yeast cells of Candida albicans [25]. Furthermore, miRNAs, especially miR155, are also involved in maintaining the proper T cell-dependent humoral response, certainly by modulating the release of cytokines and possibly through other mechanisms as well [26]. In a recent study by Iborra et al. increased miRNA expression was found in IBD, and the expression of miR192 and miR21 was also related to ulcerative colitis disease activity compared with healthy controls [23]. A prominent role, among several infective agents associated with autoimmune diseases, has been recognized for viruses and bacteria. Persistent EpsteinBarr virus (EBV) infection is linked with RA, where the EBV DNA load can increase by up to tenfold, and with SLE, where impaired T cell function was reported in addition to latently infected peripheral B cells [27]. Moreover, anti-EBV viral capsid and anti-EBV nuclear antigen 1 antibodies were also detected in almost all patients with multiple sclerosis (MS), and titers become two- to three- fold higher than those of controls during the third decade of life, increasing in line with the MS risk [28]. Concerning bacterial infections, in a prospective study, half of 246 patients with inflammatory arthritis were found positive for RF, and their anti-Proteus mirabilis IgM and IgA titers were signifi- cantly higher than those in other groups of patients. Currently, there are no studies reviewing the impact of environmental exposure to fungal antigens on autoimmunity. However, Shinohara et al. induced coronary arteritis (a hallmark of Kawasaki arteritis) in mice by intraperitoneal injection of C. albicans water-soluble fraction, and the disease has been related to the activation of the complement lectin pathway [29], possibly through mannan-binding lectin (MBL), a pattern recognition molecule [30]. MBL can bind mannan which is a fungal cell wall antigenic element notably exposed on the yeast cell surface of S. cerevisiae. The detection of ASCAs typically associated with CD, perhaps more than just an epiphenomenon, may also be implicated in the pathogenesis of IBD [31]. Interestingly, C. albicans is able to induce the production of ASCAs (but S. cerevisiae does not elicit the reverse), as tested in rabbit experimental models and as shown by immunohistochemical stains from biopsies of patients with diagnosed systemic candidiasis [32]. Immunological Aspects and Assays Yeasts are known as biological machines capable of produc- ing antigenic components for vaccines needed to elicit pro- tective immune responses. A question arises: is S. cerevisiae immunogenic itself? The use of Saccharomyces-based ther- apeutic vaccines is supported by the evidence of their ability to stimulate tumor or viral-specific CD4 and CD8 T cell responses. Heat-killed S. cerevisiae seems to be an attractive carrier because it can express different antigens and is cost- effective as it provides danger signals that lead dendritic cells (DCs) to maturation without the need of additional adjuvants. The phagocytosis of the yeast by DCs is triggered by the immunogenic cell wall molecules, such as -1,3-D- glucan and mannan, which induce critical signals usually associated with microbial infection. This event represents the first step, and it is followed by antigen degradation and the presentation of their fragments on the APC surface by MHC I and MHC II molecules, interacting with the TCR and inducing co-stimulatory signals to lead the adaptive T cell (CD8 + or CD4 + )-mediated response [33, 34]. S. cerevi- siae is an effective inducer of innate and adaptive cellular immunity, and recombinant yeast cells (GI-5005) can lead to a potent antigen-specific proliferative and cytotoxic T cell response associated with Th1-type cytokine secretion [35]. Commensals such as Saccharomyces are required for nu- trition, proper development of Peyers aggregated lymphoid tissue, and tissue healing. However, it is possible that in the proinflammatory pathological microenvironment that charac- terizes many immune-mediated diseases, notably IBD, the alteration of the finely regulated interaction between APCs, the nonclassically pathogenetic microbiota, and Th17 cells in the gut could trigger autoimmunity [20]. Moreover, MyD88, as an adaptor molecule shared by most TLRs, has been proven to play a key role in antifungal defense by several in vivo studies, underlining the relevance of TLRs in the host inter- action with fungal microbial antigens [36]. The subsequent development of the humoral immune response leads to the production by B lymphocytes and plasma cells of antibodies against the yeast, so it is not yet clear whether it might simply represent an epiphenomenon or could have a direct pathogenic role through a co- stimulatory CD80/86-CD28-mediated effect. Indeed, it is plausible that in a proinflammatory state, a mechanism of molecular mimicry involving the eukaryotic microorganism and self-antigens takes over. Furthermore, infection by C. albicans can induce the production of ASCAs in humans, while Saccharomyces does not lead to the production of antibodies to C. albicans [29]. On the other hand, concerns have been raised regarding the current safety of vaccines due to the presence of adju- vants. Since heat-killed Saccharomyces can act like com- mon adjuvants such as squalene, aluminum, and silicone (Table 1) when injected together with preventive vaccines, there is a risk of inducing an autoimmune disorder by administering Saccharomyces-based therapeutic or even preventive vaccines instead of traditional ones [3739]. It is very difficult to find the ideal compromise between im- mune system stimulation and modulation. Indeed, proce- dures used to manufacture vaccines for hepatitis B and/or hepatitis A result in products that contain no more than 1 5 % residual yeast proteins (Recombivax HB, Engerix B; Merck & Co.) [40]. Although the risk/benefit analysis still Clinic Rev Allerg Immunol indicates ensuring that vaccinations are used, we now face the challenge of developing risk-free vaccines. Indeed, an additional risk is that of developing the re- cently identified syndrome, namely, autoimmune/inflamma- tory syndrome induced by adjuvants [37] that comprises several medical conditions characterized by hyperactive im- mune responses accompanied by a similar array of signs and symptoms. Since adjuvants are the common ground that could possibly induce autoimmune or autoinflammatory diseases in humans, the use of immunogenic matter as an adjuvant, such as S. cerevisiae, should be carefully evaluated. ASCAs were found in several autoimmune diseases by means of ELISA tests used for the quantitative measurement of IgG- and IgA-class autoantibodies against mannan of S. cerevisiae in human sera or plasma. The assessment of ASCAs by ELISA resulted in 5079 % sensitivity and 74 93 % specificity in Australian CD patients, depending on the commercial kits used [41]. ASCAs are directed against the cell wall mannan (phosphopeptidomannan) of the yeast S. cerevisiae. IgG as well as IgA ASCAs are held to be highly specific for CD. However, the determination of ASCAs is also reliable in other autoimmune disorders besides CD [3]. In a normal range study with serum samples from healthy blood donors, ASCA tests for either IgG or IgA subclasses were consid- ered positive at a titer of >10 U/ml. Nevertheless, positive results should be interpreted in the light of the patients clinical status. It is recommended that each laboratory establishes its own normal and pathological Table 1 Vaccines containing S. cerevisiae as an adjuvant Vaccines containing S. cerevisiae Extract Protein DTaP-HepB-IPV (Pediatrix) Hip/Hep B (Comvax) Hep B (Engerix-B) Hep B (Recombivax) HepA/HepB (Twinrix) Meningococcal (Menveo) Pneumococcal (Prevnar) Pneumococcal (Prevnar13) Typhoid (oral Ty21a) HPV (Gardasil)
Figs. 15 Sequence bars are displayed as a group of bars in various
shades of gray, each representing a result sequence that shows the position(s) where the result sequence is similar to the input sequence. Sequence bars showtheir score range by color shade variation, according to the alignment scores color key. The most similar hits are upmost (200). Fig. 1 a Conserved domains for chain B anti-citrullinated peptide collagen type 2. Clusters of different arrowheads which belong to specific hits included in a superfamily protein domain are shown such as the heterodimer interface (polypeptide binding site) on conserved domain IgC_L that compose the conserved feature mapped on the query se- quence. b Distribution of two hits for chain B anti-citrullinated peptide collagen type 2 compared to mannan. The alignments result came from the process of matching amino acid residues from both biosequences. In this sequence matching, consistent homology was detected showing the existing degree of similarity between the considered molecular structures. Fig. 2 a Conserved domains for U2 snRNP B. Clusters of different arrowheads which belong to specific hits included in a superfamily protein domain are shown, namely, the RNA recognition motif (RRM) also known as RNA-binding domain (RBD) or ribonucleoprotein (RNP) domain, one of the most plenteous protein domains in eukaryotes. Com- positionally biased region not used in this domain database search is highlighted on the query sequence. b Distribution of the hit for U2 snRNP B compared to mannan. In this sequence match, a very high homology was detected showing the existing degree of similarity between the considered molecular structures. Fig. 3 a Conserved domains for ICAM 1 which play a central role in intercellular adhesion have been detected; the Ig2_ICAM-1-like-specific hit, included in the immunoglobulin su- perfamily protein domain, is displayed. Compositionally biased regions not used in this domain database search are highlighted on the query sequence. b Distribution of the hit for ICAM 1 compared to mannan. Fig. 4 a Conserved domains for -enolase 1, a glycolytic enzyme, have been detected compared to mannan. Clusters of different arrowheads which belong to specific hits included in the triosephosphate isomerase or TIM_phosphate_binding superfamily protein domain are shown such as dimer interface on conserved domain enolase; 37 of 37 of the residues that compose this conserved feature have been mapped to the query sequence. b Distribution of five hits for -enolase 1. In this sequence match, a very high homology was detected showing the existing degree of similarity between the considered molecular structures. Fig. 5 a Con- served domains for anti-cardiolipin/beta-2-glycoprotein-I immunoglobu- lin light chain variable region have been detected compared to mannan. Compositionally biased region not used in this domain database search is highlighted on the query sequence. b Clusters of different arrowheads which belong to specific hits included are shown. In this sequence match, a very high homology was detected showing the existing degree of similarity between the considered molecular structures such as the antigen binding site on conserved domain IgV_L_lambda where 6/6 residues that compose this conserved feature have been mapped to the query sequence Table 2 Link between rheumatoid arthritis-associated antigens and ASCAs Autoimmune disease ASCA Antigens (Homo sapiens) Comparison to mannan; accession no. EDV13046.1 IgG IgA Identities Positives Rheumatoid arthritis Neg Pos RF 5/10, 50 % 6/10, 60 % Anti-citrullinated collagen type2 3/6, 50 % 6/6, 100 % gp130-RAPS 4/5, 80 % 4/5, 80 % EIF4G1 6/8, 75 % 7/8, 88 % Bip/GRP78 5/7, 71% 5/7, 71% The main autoantigens in RAwith the highest sensitivity and specificity have been considered with the relative percentage of sequence identities and/or positive substitutions. Accession number EDV13046.1 is a code which corresponds to mannan molecular structure in the NCBI database, which was considered the referring element for each comparison RF rheumatoid factor, RAPS rheumatoid arthritis antigenic peptide- bearing soluble form, EIF4G1 eukaryotic translation initiation factor 4 gamma 1, Bip/GRP78 glucose-regulated protein 78 Clinic Rev Allerg Immunol Clinic Rev Allerg Immunol ranges for serumASCAs. The lower detection limit for ASCA ELISA was determined at 1 U/ml. The solid phase is coated with mannan from S. cerevisiae (ORG 545 ASCA IgG/IgA, ORGENTEC Diagnostika GmbH, Germany). Therefore, the ASCA test kits only recognize autoantibodies specific for this phosphopeptide [3]. Database Searching Method and Results For our purposes, we consulted the protein database of the National Center for Biotechnology Information (NCBI), com- paring mannan of Saccharomyces to several molecules with a pathogenetic role in autoimmune diseases. We focused on specific and significant results (highest identity/positivity), displaying them in tables by pathological conditions. The related graphics showthe location of the positive match, along sequence bars composed of ranges with different color shades, according to the resulting score. We also evaluated the expectation or expect value (E value); this represents the number of different alignments with scores equivalent to or better than what is expected to occur by chance in a database search. The lower the E value, the more significant is the score and the alignment [54]. The E values for our results range between 0.17 and 9.90 with a mean of 3.11. This reliability index supports and reinforces the evidence of our findings. Autoimmune Diseases Associated with S. cerevisiae The association between infectious and autoimmune diseases has been widely described, and S. cerevisiae may represent another dowel in this parquetry puzzle. In one study, ASCA IgA, IgG, and IgM levels were measured with ELISA in 30 patients affected with RA and in 152 healthy adult controls. ASCA IgA prevalence was significantly higher in RApatients (40 %) than in healthy subjects (5.3 %). In RA patients, ASCA IgA levels strongly correlated with C-reactive protein (CRP) (r=0.695; p< 0.01) and erythrocyte sedimentation rate (r=0.708; p<0.01) [6]. As shown in Table 2, we observed significant similarities be- tween the sequence of autoantigens (Fig. 1a, b) and mannan expressed by the cell wall of S. cerevisiae. In another study, serum samples from healthy volunteers (n=152) and patients with SLE (n=40) were compared for ASCA IgA, IgG, and IgM levels using ELISA. The prevalence of ASCA IgG, but not IgM and IgA, was signifi- cantly raised in active SLE patients (57.5 %) compared to healthy controls (8.5 %) (Fig. 2c). ASCA IgG levels in SLE patients during remission were relatively lower, indicating a possible correlation with disease activity [4]. Several SLE autoantigens have been found to share sequences with yeast mannan, and U2 snRNP B (Fig. 2a, b) shows the best match (Table 3). ASCAs, Autoimmunity, and Atherosclerosis The role of local and general inflammation in atherosclerosis is a major area of interest. In a casecontrol study, the ASCA IgG and IgA levels of patients with acute myocardial infarction (AMI) were compared with those of controls to investigate the possible role of ASCAs in atherosclerosis. AMI was diagnosed by electrocardiography and serial enzymes. Elevated ASCA IgA and IgG levels were found, suggesting that ASCA positiv- ity in AMI could represent a useful marker for atherosclerotic plaque instability. It might also provide a link between inflam- matory processes and increased cardiovascular risk. Interesting- ly, one of the most significant sequence matches with mannan is ICAM-1 (Fig. 3a, b). ICAM-1 and P-selectin (Table 4) are crucial molecules for transendothelial migration of leukocytes, playing an important role in the process of atherogenesis, espe- cially in patients with chronic systemic inflammatory autoim- mune diseases [42]. The role of macrophages expressing the LOX1 receptor for oxidized LDL is well-known in the patho- genesis of atherosclerosis, but more recently, a distinction has been proposed for the cells involved in the atherogenic process, especially when it is accelerated by systemic inflammatory Table 3 Link between systemic lupus erythematosus-associated anti- gens and ASCAs Autoimmune disease ASCA Antigens (H. sapiens) Comparison to mannan; accession no. EDV13046.1 IgG IgA Identities Positives Systemic lupus erythematosus Pos Neg SSA (Ro), 5/10, 50 % 6/10, 60 % SSB (La) 6/13, 46 % 9/13, 69 % snRNPSm D3 6/11, 55 % 7/11, 64 % SmN 5/15, 33 % 8/15, 53 % U2 snRNP B 5/6, 83 % 5/6, 83 % The percentages of sequence identities and/or positive substitutions can express the extent to which the protein sequences are related Table 4 Link between acute myocardial infarction-associated antigens and ASCAs Autoimmune disease ASCA Antigens (H. sapiens) Comparison to mannan; accession no. EDV13046.1 IgG IgA Identities Positives Cardiovascular diseases, acute myocardial infarction Pos Pos P-selectin 8/15, 53 % 11/15, 80 % Intercellular adhesion molecule-1 4/4, 100 % 4/4, 100 % Myosin 5/8, 63 % 7/8, 88 % The percentage of sequence identities and/or positive substitutions can express the extent to which the protein sequences are related Clinic Rev Allerg Immunol disease: type 1 (M1) macrophage cells with a proinflammatory effect (expressing high levels of CD8086, IL23, and MHC II) and type 2 CD163 + (M2) cells displaying a Th2-like phenotype (widely represented in atherosclerotic lesions of the vascular intimal layer). The M2a macrophage subtype is activated by signaling molecules such as IL-4 and IL-13 with anti- inflammatory and pro-B cell growth and activation properties. They are also characterized by the expression of mannose receptors and the production of TGF-, dectin 1, MBL, and IL-10 (among other secretory products), thus promot- ing immunoregulation, tissue remodeling, and fibrosis in- duction. Moreover, the dominance of the M1 over the M2 phenotype has been associated with progression of athero- sclerotic disease [43]. In a randomized trial, Saccharomyces boulardii oral ad- ministration in patients with heart failure (NYHA III) ameliorated gastrointestinal symptoms (constipation, postprandial fullness, flatulence, and dyspepsia), lowering CRP, leukocyte count, and echocardiographic left atrial di- ameter compared to placebo. Increased ASCA levels were also reported in several studies on Behets disease in which a prevalence of 44 % was shown in patients with intestinal involvement, compared with 3 % in patients without gastro- intestinal symptoms [44]. Alpha-enolase 1 (Fig. 4a, b) is known as an autoantigen in Behets disease with ocular involvement (uveitis). As reported in Table 5, the similarity of sequences suggests the presence of shared epitopes in different kinds of rheumatic conditions with immunologic ocular involvement. Cross-reactive epitopes on 2- glycoprotein-I (2GPI) and S. cerevisiae (Fig. 5a, b; Table 6) were also found by our group in patients with APS. Anti- 2GPI antibodies were affinity purified from ASCA- positive APS patients and were proven to bind mannan in a dose-dependent manner [2]. Encompassing different auto- immune disorders associated with ASCA positivity [5, 4553], we discovered other autoantigens that might cross-react with antibodies against mannan of S. cerevisiae (Table 7); the percentages of sequence identities (ID) and/or positive substitutions (PS) were pointed out for transgluta- minase (ID and PS 60 %) in celiac disease, GAD65 (ID 35 %, PS 57 %) and zinc transporter 8 (ID 43 %, PS 57 %) for diabetes mellitus type 1, proteinase3 (ID 57 %, PS 86 %) and myeloperoxidase (ID 71 %, PS 86 %) for vasculitis, soluble liver/pancreas antigen (ID 40 %, PS 80 %) for autoimmune hepatitis, calprotectin or protein S100-A8 for Crohns disease (ID 60 % PS 100 %), and thyroglobulin (ID 35 %, PS 52 %) and thyroid peroxidase (ID and PS 71 %) for autoimmune thyroid disease. Performing our database research of shared epitopes, we found very interesting results with regard to systemic scle- rosis (SSc) (Table 8); high percentages of sequence Table 5 Link between Behets disease, immunologic ocular disease- associated antigens, and ASCAs Autoimmune disease ASCA Antigens (H. sapiens) Comparison to mannan; accession no. EDV13046.1 IgG IgA Identities Positives Behets disease Pos Pos -Enolase 1 6/8, 75 % 6/8, 75 % Granulysin NKG5 4/7, 57 % 4/7, 57 % Immunologic ocular disease Pos Pos Rhodopsin 4/8, 50 % 5/8, 63 % Glycosamino 5/10, 50 % 7/10, 70 % Glycan Xylose kinase -Enolase 1 6/8, 75 % 6/8, 75 % Retinal S-Ag 6/12, 50 % 8/12, 67 % The percentage of sequence identities and/or positive substitutions can express the extent to which the protein sequences are related Table 6 Link between antiphospholipid syndrome-associated antigens and ASCAs Autoimmune disease ASCA Antigens (H. sapiens) Comparison to mannan; accession no. EDV13046.1 IgG IgA Identities Positives Antiphospholipid syndrome Pos Pos 2-Glycoprotein-1 precursor 7/18, 39 % 11/18, 56 % Annexin A5 5/8, 63 % 5/8, 63 % Anti-CL/-2GPI Ig light chain variable region 7/11, 64 % 8/11, 73 % The percentage of sequence identities and/or positive substitutions can express the extent to which the protein sequences are related Table 7 Link between AID-associated antigens and ASCAs Autoimmune disease ASCA Antigens (H. sapiens) Comparison to mannan; accession no. EDV13046.1 IgG IgA Identities Positives Celiac disease Neg Pos Transglutaminase 6/10, 60 % 6/10, 60 % Diabetes mellitus type 1 Pos Pos GAD65 8/23, 35 % 13/23, 57 % Zinc transporter 8 6/14, 43 % 8/14, 57 % Vasculitis Pos Pos Soluble liver/ pancreas antigen 4/10, 40 % 8/10, 80 % Crohns disease Pos Pos Calprotectin (protein S100-A8) 3/5, 60 % 5/5, 100 % Autoimmune thyroid disease Neg Pos Thyroglobulin 8/23, 35 % 12/23, 52 % Thyroid peroxidase 5/7, 71 % 5/7, 71 % The percentage of sequence identities and/or positive substitutions can express the extent to which the protein sequences are related Clinic Rev Allerg Immunol identities and/or positive substitutions were pointed out for RNA polymerase III (ID 50 %, PS 67 %), U3-snRNP or fibrillarin (ID and PS 75 %), U3sn-RNP or matrix metalloproteinase-10 (ID and PS 75 %), hU3-55 kDa (ID 71 %, PS 86 %), nucleophosmin B23 or nucleolar phospho- protein B23 or numatrin (ID 50 %, PS 88 %), and major centromere autoantigen B (ID and PS 57 %). Indeed, data suggest seeking out ASCAs in SSc (mean E value=3.77). Conclusion and Perspectives This review provides the background and the evidence needed for further studies on the ability of ASCAs to bind autoantigens in several associated diseases, at least for the highest significant results (high identity and positivity with low E values). To the best of our knowledge, this is the first review focusing on the relationships between ASCAs and autoimmune diseases, including the molecular aspects. Since S. cerevisiae is characterized by the ability to elicit an adaptive immune response, even inducing autoreactive antibody production against mannan, we wonder about the potential limitations of administering vaccines containing S. cerevisiae plus adjuvants. It is important to consider new challenges and new vaccination issues in preventive medicine. ASCAs may be present years before the diagnosis of some related autoimmune diseases as they have been retrospectively detected in the preserved blood samples of soldiers who became affected with CD years later. Even bearing in mind the fact that S. cerevisiae is a common bakers and brewers yeast, we cannot suggest a preventive yeast-free diet, but perhaps, some clinical conditions might benefit from a reduction in yeast exposure. The importance of improving and better defining the clinical use and reliability of ASCA tests in clinical prac- tice for autoimmune diseases should certainly be under- lined. ASCA positivity should be addressed in patients with different clinical courses who may deserve closer management of comorbidities, especially concerning in- creased cardiovascular risk. References 1. Sicard D, Legras JL (2011) Bread, beer and wine: yeast domesti- cation in the Saccharomyces sensu stricto complex. C R Biol 334 (3):229236 2. 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